Abstract 4551: Preclinical characterization of novel anti-CTLA-4 prodrug antibodies with an enhanced therapeutic index

Engelhardt, John J.; Akter, Raushanara; Loffredo, John T.; Bezman, Natalie; So, Paula; Tipton, Kimberly; Irving, Bryan; West, James W.; Freebern, Wendy; Bunch, Todd; Price, Karen

doi:10.1158/1538-7445.am2020-4551

Cited by 5 publications

(4 citation statements)

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“…S3) . In agreement with this, blocking or acute loss of CTLA-4 enhances Treg proliferation in vivo (12, 16, 21, 22, 23). Thus, we hypothesized that GIGA-564 would induce less Treg proliferation than ipilimumab.…”

Section: Resultssupporting

confidence: 71%

“…Despite their ability to deplete intratumoral Tregs, conventional CTLA-4 antibodies have been shown to enhance peripheral Treg levels or proliferation in murine models, cynomolgus monkeys, and patients (16, 17, 21, 22, 23). The difference in the effect of anti-CTLA-4s on peripheral and intratumoral Tregs is likely due to the amount of CTLA-4 expressed on the surface of Tregs in the periphery versus the tumor.…”

Section: Introductionmentioning

confidence: 99%

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Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy

Stone

Carter

Wagner

et al. 2021

Preprint

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Anti-CTLA-4 antibodies such as ipilimumab were among the first immune-oncology agents to show significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients and can induce severe, immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its ligands, is the primary mechanism of action for ipilimumab. In this study we present evidence that checkpoint inhibition is not a primary mechanism of action for efficacy of anti-CTLA-4 antibodies. Instead, the primary mechanism for efficacy is FcR-mediated Treg depletion in the tumor microenvironment. First, we identified a monoclonal antibody (mAb) that binds to CTLA-4 at an epitope that differs from ipilimumab’s by only a few amino acids, yet has limited checkpoint inhibitor activity. Surprisingly, the weak checkpoint inhibitor has superior anti-tumor activity compared to ipilimumab in a murine model. The weak checkpoint inhibitor also induces less Treg proliferation and has increased ability to induce in vitro FcR signaling and in vivo depletion of intratumoral Tregs. Further experiments showed that the enhanced FcR activity of the weak checkpoint inhibitor likely contributes to its enhanced anti-tumor activity. Importantly, we also showed that weak checkpoint inhibition was associated with lower toxicity in murine models. Our work suggests that new anti-CTLA-4 drugs should be optimized for Treg depletion rather than checkpoint inhibition.

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Section: Resultssupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy

Stone

Carter

Wagner

et al. 2021

Preprint

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“…BMS-986249 is a probody composed of ipilimumab (anti-CTLA-4 antibody) linked to a proprietary masking peptide that covers the active antigen-binding site of the antibody through a protease-cleavable linker ( 48 ). BMS-986249 is currently evaluated in a phase I clinical study (NCT03369223) including patients with advanced cancer in combination with nivolumab.…”

Section: Immuno-oncology Drug Development For Bone Metastasismentioning

confidence: 99%

Insights into immuno-oncology drug development landscape with focus on bone metastasis

Kähkönen,

Halleen,

MacRitchie

et al. 2023

Front. Immunol.

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Bone is among the main sites of metastasis in breast, prostate and other major cancers. Bone metastases remain incurable causing high mortality, severe skeletal-related effects and decreased quality of life. Despite the success of immunotherapies in oncology, no immunotherapies are approved for bone metastasis and no clear benefit has been observed with approved immunotherapies in treatment of bone metastatic disease. Therefore, it is crucial to consider unique features of tumor microenvironment in bone metastasis when developing novel therapies. The vicious cycle of bone metastasis, referring to crosstalk between tumor and bone cells that enables the tumor cells to grow in the bone microenvironment, is a well-established concept. Very recently, a novel osteoimmuno-oncology (OIO) concept was introduced to the scientific community. OIO emphasizes the significance of interactions between tumor, immune and bone cells in promoting tumor growth in bone metastasis, and it can be used to reveal the most promising targets for bone metastasis. In order to provide an insight into the current immuno-oncology drug development landscape, we used 1stOncology database, a cancer drug development resource to identify novel immunotherapies in preclinical or clinical development for breast and prostate cancer bone metastasis. Based on the database search, 24 immunotherapies were identified in preclinical or clinical development that included evaluation of effects on bone metastasis. This review provides an insight to novel immuno-oncology drug development in the context of bone metastasis. Bone metastases can be approached using different modalities, and tumor microenvironment in bone provides many potential targets for bone metastasis. Noting current increasing interest in the field of OIO, more therapeutic opportunities that primarily target bone metastasis are expected in the future.

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“…In an early-phase clinical trial, the anti-CTLA4 masked antibody BMS-986249 was administered alone and in combination with nivolumab. Although higher doses of BMS-986249 could be given than what is deemed safe with the anti-CTLA4 antibody ipilimumab, there was still a 74% rate of treatment-related adverse events with the combination ( 6 ). Tumor-targeted bispecifi c antibodies combine a tumor antigen-binding site with an immune binding domain.…”

mentioning

confidence: 99%

Conditional Cancer Immunotherapy as a Safer Way to Step on the Gas

Keenan

Fong

2021

Cancer Discovery

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Abstract 4551: Preclinical characterization of novel anti-CTLA-4 prodrug antibodies with an enhanced therapeutic index

Cited by 5 publications

References 0 publications

Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy

Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy

Insights into immuno-oncology drug development landscape with focus on bone metastasis

Conditional Cancer Immunotherapy as a Safer Way to Step on the Gas

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